Diuretic 1, 4, 9(11)-pregnatrienes



United States Patent 3,284,477 DIURETIC 1,4,9(11)-PREGNATRIENES RichardC. Rausser, Union, and Eugene P. Oliveto, Glen Ridge, NJ., assiguors toSchering Corporation, Bloomfield, N.J., a corporation of New Jersey NoDrawing. Filed July 10, 1963, Ser. No. 294,150 5 Claims. (Cl.260-397.45)

This invention relates to a new series of steroidal trienes and tomethods for their preparation. More particularly, this invention relatesto certain unique 16aand 16fl-1ower alkyl substituted1,4,9(11)-pregnatrienes which are useful not only as intermediates inthe preparation of 9a-halo-l6(a or }8)-lower alkyl derivatives ofprednisone, prednosolone and the 21-esters thereof, but themselvesdisplay physiological activity.

The novel compounds of this invention may be represented by thefollowing formula:

wherein R represents lower alkyl (preferably methyl) and R represents Hor lower alkanoyl.

The novel compounds of this invention are prepared from a 16(a or[3)-lower alkyl prednisolone 21-acylate by dehydration of the ll-hydroxygroup so as to yield the corresponding 9(11)-triene. Preparation of thestarting materials and their conversion into the trienes of thisinvention is fully disclosed in copending United States applicationSerial No. 733,843, filed May 8, 1958, now United States Patent3,164,618, issued January 5, 1965, of which the instant application is:a continuation-impart.

Also disclosed in said copending application are processes forconverting the trienes of this invention into the aforementioned9oa-halo-16(a or ;3)-lower alkyl derivatives of prednisone, prednisoloneand the 21-esters thereof. These compounds, and particularly 16(01. orp3)-methyl-9afiuoroprednisolone and its 21-esters, .are potentanti-inflammatory agents useful in the treatment of rheumatoid arthritisand other diseases requiring adrenocorticoid therapy.

In addition to their value as intermediates, the novel trienes of thisinvention surprisingly have been found to display physio-logicalactivity as diuretic agents. Administration of these trienes results ina marked increase in the urinary elimination of water. The trienes ofthis invention, therefore, are valuable therapeutic agents for thetreatment and control of edmatic conditions.

In general, dehydration of the ll-hydroxylated starting material iseffected by treating said starting material (16cc or lop-methylprednisolone acetate for example) with an alkyl or aryl sulfonylchloride (.methane-sulfonyl chloride or p-toluene-sulfonyl chloride forexample) in alkaline organic media (pyridine for example) at roomtemperature for 5 to 6 hours. The reaction mixture is then poured into amixture of ice and strong acid (hydrochloric acid for example) and thesolid triene-Zl-acetate so produced is separated by filtration andpurified by recrystallization from a suitable organic solvent (acetone,hexane or a mixture thereof for example).

"ice

Where the free alcohol is desired, the 2l-acetate as prepared above isreacted with standard hydrolytic agents (aqueous methanolic sodium orpotassium bicarbonate, sodium hydroxide, sodium carbonate or sodiumalkoxide such as sodium ethoxide for example). The hydrolysis may becarried out by refluxing the acetate and the hydrolytic agent in asuitable organic solvent, methanol for example) for approximately /2hour. The reaction mixture is concentrated to approximately /2 thevolume in vacuo and water is added. The precipitated 21-01 is fil-'tered, dried and purified by recrystallization from a suitable organicsolvent (methanol for example). The free alcohols, where desired, may bere-esterified at C-21 by treatment with any desired lower alkanoylacylating agent according to conventional processes.

The following examples will more fully illustrate the best modecontemplated by applicants for carrying out their invention:

EXAMPLE 1 16a-methyl-1,4,9 (11 -pregriatriene'-1 t-21-diOl-3,20-

dione 21 acetate To a solution of 0.5 g. of 16u-methyl-1,4-pregnadiene-1lfl,17u,21-triol-3,20-dione 21-acetate in 3.0 ml. of pyridine add withstirring 0.3 ml. of methane-sulfonyl chloride in 4.0 of pyridine. Stirthe mixture at roomtemperature for 6 hours, then pour intoice-hydrochloric acid. Remove the precipitate by filtration andrecrystallize from acetone-hexane.

EXAMPLE 2 1 6u-m'ethyl-1 ,4,9 (11 )-pregnatriene-1 711,21-di0l-3,20-di0ne Dissolve 0.5 g. ofl6u-methyl-1,4,9(ll)-pregnatrienel7a,2l-diO1-3,20 di0116 21-acetate in20.0 ml. of methanol and 2.0 ml. of water containing 0.1 g. of potassiumb-icarbonate. Refiux the solution for /2 hour, then concentrate to /2the volume in vacuo. Add water and recover the resulting precipitate byfiltration. Recrystallize from methanol.

EXAMPLE 3 1 6,8-mcthyl-1,4,9(1 1 -pregmatriene-1 7u,21-diol-3,20-di0ne21 acetate At room temperature stir for 5 hours a mixaure of 0.5 g. of1613 methyl-1,4-pregnadiene-11,8,17a,2l-tri0l- 3,20-dione Zl-acetate in3.0 ml. of pyridine and 0.3 ml. of methane-sulfonyl chloride in 4.0 ml.of pyridine. Pour the mixture into ice-hydrochloric acid and separatethe resulting precipitate by filtration. Recrystallize from acetone.

EXAMPLE 4 1 6B-mcthyl-1,4,9 (11 -pregnatriene-1 7 04,21 -di0l-3,20-di0neDissolve 0.5 g. of 16/3-methyl-1,4,9(11)-pregnatriene- 1704,21-dlOl-3,20-di01'16 2l-acetate in 20.0 ml. of methanol and 2.0 ml.of water. After refluxing the solution for approximately /2 hour,concentrate to /2 the volume in vacuo and add water. Recover theresulting precipitate by filtration and recrystallize from methanol.

The foregoing examples illustrate the preparation of 16aand l6fi methylcompounds. Similarly, :by starting with other 16(oc or 5) -lower alkylderivatives of prednisolone 2l-acy1-ate, such as ethyl, butyl, and thelike, the corresponding 16-lower alkyl-2l-acylate or free alcohol may beprepared. These, and other 16-lower alkyl derivatives, are alsodescribed in the aforementioned copending application.

3 4 The subject matter which applicants regard as their 3.16a-methy1-1,4,9(11)-pregnatriene 17a,21 diolinvention is particularlypointed out and distinctly claimed 3,20-dione. as follows: 4-. 16;3methyl-1,4,9(11)-pregnatriene-17a,21-di0l-3,20-

1. A compound having the formula: dione ZI-acetate.

5 5. 16 3-methy1-1,4,9(11)-pnegnatriene 170:,21 diolf 3,20-dione. 0:0--0H References Cited by the Examiner Q R UNITED STATES PATENTS 103,004,994 10/1961 Arth et a1 260397.45

OTHER REFERENCES Fried et 111., J. Amer. Chem. Soc., 77, pp. 4181 and 154182 (1955).

oll

'wherein R is a lower alkyl group and R is a member of the groupconsisting of H and lower alkanoyl. I GOTTS P E 2.16a-methyl-1,4,9(11)-pregnatriene 1701,21 diol- LEW S xammer 3,20-dione21-acetate. T. M. MESHBESHER, Assistant Examiner.

1. A COMPOUND HAVING THE FORMULA:16-R,17-(HO-),17-(R1-O-CH2-CO-)-1,4,9(11)-ANDROSTATRIEN3-ONE WHEREIN RIS A LOWER ALKYL GROUP AND R1 IS A MEMBER OF THE GROUP CONSISTING OF HAND LOWER ALKANOYL.